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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneous and complex genetic underpinnings. Our previous microarray gene expression profiling identified significantly different neuregulin-2 gene (NRG2) expression between ASD patients and controls. Thus, we aimed to clarify whether NRG2 is a candidate gene associated with ASD. The study consisted of two stages. First, we used real-time quantitative PCR in 20 ASDs and 20 controls to confirm the microarray gene expression profiling results. The average NRG2 gene expression level in patients with ASD (3.23 ± 2.80) was significantly lower than that in the controls (9.27 ± 4.78, p < 0.001). Next, we conducted resequencing of all the exons of NRG2 in a sample of 349 individuals with ASD, aiming to identify variants of the NRG2 associated with ASD. We identified three variants, including two single nucleotide variants (SNVs), IVS3 + 13A > G (rs889022) and IVS10 + 32T > A (rs182642591), and one small deletion at exon 11 of NRG2 (delGCCCGG, rs933769137). Using data from the Taiwan Biobank as the controls, we found no significant differences in allele frequencies of rs889022 and rs182642591 between two groups. However, there is a significant difference in the genotype and allele frequency distribution of rs933769137 between ASDs and controls (p < 0.0001). The small deletion is located in the EGF-like domain at the C-terminal of the NRG2 precursor protein. Our findings suggest that NRG2 might be a susceptibility gene for ASD.
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Trastorno del Espectro Autista , Predisposición Genética a la Enfermedad , Neurregulinas , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Trastorno del Espectro Autista/genética , Estudios de Casos y Controles , Exones/genética , Perfilación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Factores de Crecimiento Nervioso , Neurregulinas/genética , Neurregulinas/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
Arc/Arg3.1 (activity-regulated cytoskeletal-associated protein (ARC)) is a critical regulator of long-term synaptic plasticity and is involved in the pathophysiology of schizophrenia. The functions and mechanisms of human ARC action are poorly understood and worthy of further investigation. To investigate the function of the ARC gene in vitro, we generated an ARC-knockout (KO) HEK293 cell line via CRISPR/Cas9-mediated gene editing and conducted RNA sequencing and label-free LC-MS/MS analysis to identify the differentially expressed genes and proteins in isogenic ARC-KO HEK293 cells. Furthermore, we used bioluminescence resonance energy transfer (BRET) assays to detect interactions between the ARC protein and differentially expressed proteins. Genetic deletion of ARC disturbed multiple genes involved in the extracellular matrix and synaptic membrane. Seven proteins (HSPA1A, ENO1, VCP, HMGCS1, ALDH1B1, FSCN1, and HINT2) were found to be differentially expressed between ARC-KO cells and ARC wild-type cells. BRET assay results showed that ARC interacted with PSD95 and HSPA1A. Overall, we found that ARC regulates the differential expression of genes involved in the extracellular matrix, synaptic membrane, and heat shock protein family. The transcriptomic and proteomic profiles of ARC-KO HEK293 cells presented here provide new evidence for the mechanisms underlying the effects of ARC and molecular pathways involved in schizophrenia pathophysiology.
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Proteómica , Transcriptoma , Sistemas CRISPR-Cas , Proteínas Portadoras , Cromatografía Liquida , Células HEK293 , Humanos , Proteínas de Microfilamentos , Proteínas Mitocondriales , Espectrometría de Masas en TándemRESUMEN
Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.
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Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Adulto , Variaciones en el Número de Copia de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Heroin dependence is a complex mental disorder resulting from interactions between genetic and environmental factors. Identifying the susceptibility genes of heroin dependence is the basis for understanding the pathogenesis of heroin dependence. Using a total gene expression microarray, we detected 924 differentially expressed gene transcripts in lymphoblastoid cell lines (LCLs) between 19 male heroin-dependent individuals and 20 male control subjects, including 279 upregulated and 645 downregulated gene transcripts in heroin-dependent individuals. We verified the reduced expression of the neuron-specific enolase gene (ENO2) in heroin-dependent individuals using real-time quantitative polymerase chain reaction and Western blot analysis. We further compared the allele and genotype frequencies of three single nucleotide polymorphisms (SNPs, rs11064464, rs3213433 and rs10849541) of the ENO2 gene between 532 male heroin-dependent individuals and 369 male controls. No significant differences in the allele or genotype frequencies of these three SNPs were detected between these two groups. Nevertheless, we identified a haplotype (T-C-G) derived from these three SNPs significantly underrepresented in heroin-dependent individuals compared with the control group (72.7% versus 75.9%, P<0.032), while two other rare haplotypes (C-A-G and T-C-A) significantly overrepresented in heroin-dependent individuals compared with the control group (P<0.001). Further study, however, did not detect significant differences of the plasma concentration of neuron-specific enolase between these two groups. Our data suggest that the ENO2 gene might be associated with heroin dependence, and reduced ENO2 gene expression may confer increased risk to heroin dependence.
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Perfilación de la Expresión Génica/métodos , Predisposición Genética a la Enfermedad/genética , Dependencia de Heroína/genética , Fosfopiruvato Hidratasa/genética , ARN Mensajero/genética , Western Blotting , Estudios de Casos y Controles , Línea Celular , Frecuencia de los Genes , Interacción Gen-Ambiente , Estudios de Asociación Genética , Haplotipos/genética , Hemoglobinas/metabolismo , Humanos , Linfocitos/citología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fosfopiruvato Hidratasa/sangre , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple/genética , TaiwánRESUMEN
Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution.
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Moléculas de Adhesión Celular Neuronal/genética , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Adulto , Western Blotting , Agregación Celular/genética , Agregación Celular/fisiología , Línea Celular , Electrofisiología , Femenino , Humanos , Inmunohistoquímica , Masculino , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción/genéticaRESUMEN
OBJECTIVE: The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors significantly regulate the synaptic transmission and functions of various synaptic receptors. This study aimed to identify single nucleotide mutations in the glutamate receptor, ionotropic, AMPA type (GRIA) gene family, which is associated with schizophrenia. METHODS: The exon regions of four genes (GRIA1, GRIA2, GRIA3, and GRIA4) encoding glutamate ionotropic receptor AMPA type proteins were resequenced in 516 patients with schizophrenia. We analyzed the protein function of the identified rare mutants via immunoblotting. RESULTS: A total of 24 coding variants were detected in the GRIA gene family, including six missense mutations, 17 synonymous mutations, and one frameshift insertion. Notably, three ultra-rare missense mutations (GRIA1p.V182A, GRIA2p.P123Q, and GRIA4p.Y491H) were not documented in the single nucleotide polymorphism database, gnomAD genomes, and 1517 healthy controls available from Taiwan BioBank. Immunoblotting revealed GRIA4p.Y491H mutant with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that, in some patients affected by schizophrenia, the GRIA gene family harbors rare functional mutations, which support rare coding variants that could contribute to the genetic architecture of this illness. The in-vitro impacts of these rare pathological mutations on the pathophysiology of schizophrenia are worthy of future investigation.
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Esquizofrenia , Humanos , Esquizofrenia/genética , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico , Ácido Glutámico , Mutación Missense/genética , ExonesRESUMEN
Schizophrenia (SCZ) is a complex psychiatric disorder with high heritability; identifying risk genes is essential for deciphering the disorder's pathogenesis and developing novel treatments. Using whole-exome sequencing, we screened for mutations within protein-coding sequences in a single family of patients with SCZ. In a pathway enrichment analysis, we found multiple transmitted variant genes associated with two KEGG pathways: herpes simplex virus 1 (HSV1) infection and the extracellular matrix (ECM)-receptor interaction. When searching for rare variants, six variants, SLC6A19p.L541R, CYP2E1p.T376S, NAT10p.E811D, N4BP1p.L7V, CBX2p.S520C, and ZNF460p.K190E, segregated with SCZ. A bioinformatic analysis showed that three of these mutated genes were associated with chromatin modulation. We found that HSV1 infection, ECM-receptor interaction pathways, and epigenetic mechanisms may contribute to the pathogenesis of SCZ in certain families. The identified polygenetic risk factors from the sample family provide distinctive underlying biological mechanisms of the pathophysiology of SCZ and may be useful in clinical practice and patient care.
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OBJECTIVE: Studies showed that rare copy number variations (CNVs) encompassing the vasoactive intestinal peptide receptor 2 gene (VIPR2) were associated with schizophrenia, indicating VIPR2 is a risk gene for schizophrenia. We hypothesized that besides CNV, rare pathogenic single-nucleotide variant (SNV) or small insertion/deletion (Indel) of VIPR2 might be present in some patients and contribute to the pathogenesis of schizophrenia. METHODS: We performed genome-wide CNV analysis to screen CNV at the VIPR2 locus and targeted sequencing of all the exons of VIPR2 to search for SNV and indel in a sample of patients with chronic schizophrenia from Taiwan. RESULTS: We detected a 230-kb microduplication encompassing the VIPR2 in 1 out of 200 patients. Furthermore, we identified six ultrarare SNVs, including one splicing SNV and five missense SNVs, in 516 patients. In-silico analyses showed these SNVs had a damaging effect on the function of VIPR2. CONCLUSION: Our findings support the idea that besides CNV, rare pathogenic SNVs of VIPR2 might contribute to the pathogenesis of schizophrenia in some patients.
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Receptores de Tipo II del Péptido Intestinal Vasoactivo , Esquizofrenia , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Humanos , Mutación , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Esquizofrenia/genética , TaiwánRESUMEN
Schizophrenia is a complex mental disorder with a genetic component. The GRIK gene family encodes ionotropic glutamate receptors of the kainate subtype, which are considered candidate genes for schizophrenia. We screened for rare and pathogenic mutations in the protein-coding sequences of the GRIK gene family in 516 unrelated patients with schizophrenia using the ion semiconductor sequencing method. We identified 44 protein-altered variants, and in silico analysis indicated that 36 of these mutations were rare and damaging or pathological based on putative protein function. Notably, we identified four truncating mutations, including two frameshift deletion mutations (GRIK1p.Phe24fs and GRIK1p.Thr882fs) and two nonsense mutations (GRIK2p.Arg300Ter and GRIK4p.Gln342Ter) in four unrelated patients with schizophrenia. They exhibited minor allele frequencies of less than 0.01% and were absent in 1517 healthy controls from Taiwan Biobank. Functional analysis identified these four truncating mutants as loss-of-function (LoF) mutants in HEK-293 cells. We also showed that three mutations (GRIK1p.Phe24fs, GRIK1p.Thr882fs, and GRIK2p.Arg300Ter) weakened the interaction with the PSD95 protein. The results suggest that the GRIK gene family harbors ultrarare LoF mutations in some patients with schizophrenia. The identification of proteins that interact with the kainate receptors will be essential to determine kainate receptor-mediated signaling in the brain.
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GNB1L haploinsufficiency caused by 22q11.2 deletion syndrome may contribute to schizophrenia pathophysiology. We resequenced the protein-coding sequences of GNB1L in 553 patients with schizophrenia and 535 controls from Taiwan. Four common single-nucleotide polymorphisms showed no association with patients with schizophrenia. We identified 17 rare missense mutations, including three that were schizophrenia-associated and predicted as pathogenic (p.R57W, p.G68S, and p.R265C). Given that rare mutations with high penetrance contribute to schizophrenia, missense mutations of GNB1L might increase the risk of schizophrenia in some patients.
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Síndrome de DiGeorge , Péptidos y Proteínas de Señalización Intracelular/genética , Esquizofrenia , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Esquizofrenia/genéticaRESUMEN
Schizophrenia is a chronic, devastating mental disorder with complex genetic components. Given the advancements in the molecular genetic research of schizophrenia in recent years, there is still a lack of genetic tests that can be used in clinical settings. Chromosomal microarray analysis (CMA) has been used as first-tier genetic testing for congenital abnormalities, developmental delay, and autism spectrum disorders. This study attempted to gain some experience in applying chromosomal microarray analysis as a first-tier genetic test for patients with schizophrenia. We consecutively enrolled patients with schizophrenia spectrum disorder from a clinical setting and conducted genome-wide copy number variation (CNV) analysis using a chromosomal microarray platform. We followed the 2020 "Technical Standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)" to interpret the clinical significance of CNVs detected from patients. We recruited a total of 60 patients (36 females and 24 males) into this study. We detected three pathogenic CNVs and one likely pathogenic CNV in four patients, respectively. The detection rate was 6.7% (4/60, 95% CI: 0.004-0.13), comparable with previous studies in the literature. Also, we detected thirteen CNVs classified as uncertain clinical significance in nine patients. Detecting these CNVs can help establish the molecular genetic diagnosis of schizophrenia patients and provide helpful information for genetic counseling and clinical management. Also, it can increase our understanding of the pathogenesis of schizophrenia. Hence, we suggest CMA is a valuable genetic tool and considered first-tier genetic testing for schizophrenia spectrum disorders in clinical settings.
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NR2E1 is implicated in the regulation of neurogenesis and considered as a candidate gene for schizophrenia. We resequenced all the exons of NR2E1 in 547 patients with schizophrenia and 567 controls from Taiwan. We identified five common SNPs with no association with patients with schizophrenia. Further haplotype-based association analysis showed that two haplotypes within NR2E1 were correlated with the schizophrenia risk. Four rare mutations located at untranslated regions were identified in patients with schizophrenia but not in our control sample. The present study suggests that NR2E1 is likely to play a significant role in conferring susceptibility to schizophrenia.
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Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Receptores Citoplasmáticos y Nucleares/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Adulto , Exones/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Receptores Nucleares Huérfanos , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/epidemiología , Taiwán/epidemiologíaRESUMEN
Deleterious mutations of MECP2 are responsible for Rett syndrome, a severe X-linked childhood neurodevelopmental disorder predominates in females, male patients are considered fatal. However, increasing reports indicate that some MECP2 mutations may also present various neuropsychiatric phenotypes, including intellectual disability, autism spectrum disorder, depression, cocaine addiction, and schizophrenia in both males and females, suggesting varied clinical expressivity in some MECP2 mutations. Most of the MECP2 mutations are private de novo mutations. To understand whether MECP2 mutations are associated with schizophrenia, we systematically screen for mutations at the protein-coding regions of the MECP2 gene in a sample of 404 schizophrenic patients (171 females, 233 males) and 390 non-psychotic controls (171 females, 218 males). We identified six rare missense mutations in this sample, including T197M in one male patient and two female controls, L201V in nine patients (three males and six females) and 4 controls (three females and one male), L213V in one female patient, A358T in one male patient and one female control, P376S in one female patient, and P419S in one male patient. These mutations had been reported to be present in patients with various neuropsychiatric disorders other than Rett syndrome in the literature. Furthermore, we detected a novel double-missense mutation P376S-P419R in a male patient. The family study revealed that his affected sister also had this mutation. The mutation was transmitted from their mother who had a mild cognitive deficit. Our findings suggest that rare MECP2 mutations exist in some schizophrenia patients and the MECP2 gene could be considered a risk gene of schizophrenia.
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OBJECTIVE: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia. METHODS: We resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry. RESULTS: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.
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Valproic acid (VPA) is a multifunctional medication used for the treatment of epilepsy, mania associated with bipolar disorder, and migraine. The pharmacological effects of VPA involve a variety of neurotransmitter and cell signaling systems, but the molecular mechanisms underlying its clinical efficacy is to date largely unknown. In this study, we used the isobaric tags for relative and absolute quantitation shotgun proteomic analysis to screen differentially expressed proteins in VPA-treated SH-SY5Y cells. We identified changes in the expression levels of multiple proteins involved in Alzheimer's disease, Parkinson's disease, chromatin remodeling, controlling gene expression via the vitamin D receptor, ribosome biogenesis, ubiquitin-mediated proteolysis, and the mitochondrial oxidative phosphorylation and electron transport chain. Our data indicate that VPA may modulate the differential expression of proteins involved in mitochondrial function and vitamin D receptor-mediated chromatin transcriptional regulation and proteins implicated in the pathogenesis of neurodegenerative diseases.
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EGR1, involved in the regulation of synaptic plasticity, learning, and memory, is considered a candidate gene for schizophrenia. We resequenced the exonic regions of EGR1 in 516 patients with schizophrenia and conducted a reporter gene assay. We found two mutations including a rare mutation (c.-8C>T, rs561524195) and one common SNP (c.308-42C>T, rs11743810). The reporter gene assay showed c.-8C>T mutant did not affect promoter activity. Gene expression analyses showed that the average EGR1 mRNA and protein levels in lymphoblastoid cell lines of schizophrenia in male, but not female, were significantly higher than those in controls. We conducted in vitro DNA methylation reaction, luciferase activity assay, and pyrosequencing to assess DNA methylation of EGR1 expression underlying the pathophysiology of schizophrenia. DNA methylation of the EGR1 promoter region attenuated reporter activity, suggesting that DNA methylation regulates EGR1 expression. There were no statistically significant differences in DNA methylation levels of 17 CpG sites at the EGR1 promoter region between 64 patients with schizophrenia compared with 64 controls. These results suggest that the exonic mutations in EGR1 and DNA methylation regulating EGR1 expression might not be associated with schizophrenia. However, the gender-specific association of elevated EGR1 expression might be involved in the pathophysiology of schizophrenia.
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Metilación de ADN , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Línea Celular , Islas de CpG/genética , Exones , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Mutación , Regiones Promotoras Genéticas/genética , ARN Mensajero/metabolismo , Esquizofrenia/fisiopatología , Factores SexualesRESUMEN
Aberrant WNT signaling has been implicated in the pathophysiology of schizophrenia. WNT7A, a member of the WNT gene family, is considered a potential candidate of schizophrenia. All exons of WNT7A in 570 schizophrenic patients and 563 controls were sequenced, and protein functional analysis was conducted. Five common variants were identified, but none were noted to be associated with schizophrenia. Nevertheless, nine rare mutations, including one schizophrenia-specific missense mutation (c.305Gâ¯>â¯A), were discovered. However, immunoblot analysis findings revealed that the c.305Gâ¯>â¯A mutation did not affect protein expression. These results suggest that WNT7A is unlikely to be associated with susceptibility to schizophrenia.
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Análisis Mutacional de ADN/métodos , Mutación/genética , Esquizofrenia/genética , Proteínas Wnt/genética , Estudios de Cohortes , Exones/genética , Femenino , Células HEK293 , Humanos , Masculino , Mutación Missense/genética , Esquizofrenia/diagnósticoRESUMEN
Synaptogyrin 1 gene (SYNGR1) is considered as a positional candidate gene for schizophrenia because of its location at chromosome 22q13, a region linked to schizophrenia, and its reduced expression in postmortem brain of patients with schizophrenia. Additionally, genetic studies also reported association of SYNGR1 is with schizophrenia and bipolar disorder in southern India. Prompted by these findings, we were interested to know if SYNGR1 is also associated with schizophrenia in our population. Therefore, we systematically searched for SYNGR1 mutations in a cohort of Han Chinese patients from Taiwan. Four single nucleotide polymorphisms (SNPs) were identified, including three at the putative core promoter region (g.-673A>C, g.-377G>A and g.-318G>T) that are in strong linkage disequilibrium and one in intron 2 (IVS2-64C>G). Computer program predicts that g.-637A>C and g.318G>T may change transcription binding sites of AP-1 and TGT3, respectively. We further carried out SNP- and haplotype-based case-control association studies of these tress SNPs with schizophrenia. However, no association was detected between these SNPs and schizophrenia in our sample. Nevertheless, we identified several rare mutations in exon 6 of SYNGR1 gene in our patient cohort (n=497), including a 3-bp (AAC) in-frame insertion between codon 202 and 203 (P202_T203insN) in two patients, an A-to-G missense mutation (c.665A>G) at codon 222 (D222G) in one patient, a synonymous mutation (c.669C>T) at codon 223 (T223T) in one patient, and a C-to-T at 3' UTR of SYNGR1 (c.772C>T) in one patient. These are mutations were not found in 507 control subjects, suggesting further functional assays are warranted to verify their relevance to the pathogenesis of schizophrenia.
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Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Adulto , Pueblo Asiatico , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , SinaptogirinasRESUMEN
DNA methylation has been implicated in the pathogenesis of schizophrenia. EGR3 is considered as a potential candidate gene for schizophrenia. We conducted in vitro DNA methylation reaction, Lucia luciferase activity assay, and pyrosequencing assay to assess the DNA methylation of the EGR3 expression underlying the pathophysiology of schizophrenia. We found that DNA methylation of the putative EGR3 regulatory regions attenuated Lucia luciferase activity. There was no difference in the DNA methylation pattern of EGR3 between in 50 schizophrenic patients and 47 controls. Our data suggest that DNA methylation regulated the expression of EGR3 might not be associated with schizophrenia.
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Metilación de ADN/genética , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Femenino , Humanos , Masculino , Regiones Promotoras Genéticas/genéticaRESUMEN
Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies on the detection of specific autoantibodies in the blood or cerebral spinal fluid in addition to the clinical presentations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our patients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample collected from patients with the first-episode schizophrenia. The six autoantibodies including antibodies against N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, γ-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 females) were investigated; however, no positive case was identified. In this second study, we screened anti-NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and 101 males) including 48 patients defined as treatment resistance. None of this sample was detected as positive. The negative findings in this study suggest that the seroprevalence of autoantibodies against neuronal surface proteins might be low in patients diagnosed with schizophrenia.